• Jean Baum
  • Distinguished Professor
  • Research Synopsis: Structural studies of proteins by nuclear magnetic resonance techniques
  • Phone: (848) 445-5666




1. Collagen-Protein Interaction

Collagen is the most abundant protein of the human body. It provides structural integrity in the human body and is responsible for multiple interactions with cells and other matrix molecules. Many common diseases, such as arthritis, diabetes, and cancer involve abnormal regulation or reactivity of collagen, and certain genetic diseases that arise from collagen mutations result in connective tissue disease or aortic aneurism. Although the collagen triple helix has a relatively uniform rod-like structure, with an amino acid sequence of (Gly-X-Y)n repeats, subtle alterations in structure and dynamics along the collagen chain are critical to many biological events. It is outstanding how proteins can recognize specific sites in collagen and how a simple Gly mutation on collagen sequence can lead to severe diseases. Our laboratory uses an integrated approach based on NMR in conjunction with computational, biophysical and biological methods to provide unique structural and dynamic insight into protein recognition of collagen and to understand the molecular basis of collagen diseases arising from mutations.

Collagen Integrin Receptors

The binding of integrins to collagen plays a critical role in numerous cellular adhesion processes including platelet activation and aggregation, a key process in clot formation, and cancer metastasis. The two major integrin receptors, α1β1 and α2β1, bind collagen through their α1 and α2 I-domain. The binding is specific with variable affinities, depending on the collagen sequence as well as the integrin protein. Our research focuses on addressing the following questions:

  • How does the integrin I-domain select, recognize and bind collagen?
  • How do two structurally similar proteins like α1β1 and α2β1 integrins prefer different collagen subtypes and different collagen sequences?
  • What makes a certain collagen sequence a high or low affinity sequence for integrin binding?

Collagen mutations: Osteogenesis Imperfecta disease

The substitution of a single Gly by another amino acid breaks the characteristic repeating (Gly-X-Y)n sequence pattern of collagen and results in connective tissue disease. Osteogenesis Imperfecta (OI) is characterized by brittle bones and results in lethal to non-lethal phenotypes. Our goal is to characterize the structure and dynamics of Gly -> X substitutions that result in OI disease and to be able to predict OI phenotype based on sequence analysis using an integrative approach that includes NMR, bioinformatics, MD simulations and stability measurements. To achieve this, we base our research in the following:

  • Development of novel methodology designed to achieve better structural and dynamic characterization of the collagen model peptides.
  • Bioinformatics analyses of Type I collagen sequences to obtain local consensus sequence patterns that describe lethal and nonlethal OI;
  • Structural and dynamic characterization of lethal and nonlethal collagen sequences by NMR to try correlate these to OI phenotype.


2. Protein Aggregation

Many devastating neurodegenerative diseases are associated with the transformation of protein from their normal soluble forms to amyloid fibrils. Upon amyloidogenesis these proteins accumulate in the brain and cause diseases such as Parkinson's, Alzheimer's, type II diabetes, and Huntington's disease. α-synuclein is a “natively unfolded” 14kD protein of unknown function that has been implicated in Parkinson's disease pathogenesis. Numerous studies have established the in vitro conversion of unfolded α-synuclein to a filamentous β-sheet aggregate. Despite exhaustive research efforts, the mechanism by which α-synuclein transforms, from a soluble unfolded protein to an insoluble aggregate, remain unclear. There is increasing evidence that small protein oligomers may be more toxic than the final fibrillar aggregates. Therefore it is critically important to characterize the species formed during the very early stages of aggregation. Our laboratory uses several techniques like NMR, fluorescence, electron microscopy, circular dichroism and computational methods to try to elucidate the initial stages of the α-synuclein aggregation mechanism.

α-synuclein aggregation and oxidative stress

Very recently, it has been shown that in vivo, α-synuclein undergoes a co-translational modification, acetylation, in the N-terminus. This modification has been suggested to increase α-synuclein oligomerization states. The existence of these oligomeric states due to acetylation might interfere with the accepted aggregation view of aS. The impact of acetylation on α-synuclein function and aggregation is still not fully understood. This discovery raises new questions:

  • How do the in vivo acetylation influences α-synuclein aggregation?
  • What are the timescales of the fluctuations and the extent of residual secondary structure in the different species and how do these relate to the rate of fibril formation?
  • Does oxidative stress increases α-synuclein aggregation?

We are characterizing the acetylated α-synuclein and comparing it to the non-acetylated form to try to elucidate the real aggregation mechanism that occurs in vivo.

α-synuclein homologs and interactions

β-synuclein is a neuroprotective protein co-localized with α-synuclein in brain cells. Despite the sequence similarity to α-synuclein this protein does not aggregate. Interestingly, β-synuclein not only does not aggregate by itself, but it can also inhibit α-synuclein aggregation. However, a simple single point mutation in β-synuclein sequence causes it to aggregate, leading to dementia with Lewy Bodies (DLB) disease. It is still unknown how β-synuclein is able to inhibit α-synuclein aggregation or even how its mutants induce β-synuclein to aggregate. Using a multidisciplinary approach our laboratory is trying to uncover the β-synuclein neuroprotective mechanism.


Moriarty, G.M., C. Minetti, D.P. Remeta, and J. Baum. “A Revised Picture of the Cu(II) α-Synuclein Complex: The Role of N-Terminal Acetylation", in press, Biochemistry (2014).

Moriarty, G.M., M.K. Janowska, L. Kang, and J. Baum. “Exploring the accessible conformations of N-terminal acetylated α-synuclein”, FEBS Lett., 587(8), 1128-38 (2013).

Kang, L., M.K. Janowska, G.M. Moriarty, and J. Baum. “Mechanistic insight into the relationship between N-terminal acetylation of α-synuclein and fibril formation rates by NMR and fluorescence”, PLoS One, 8(9), e75018 (2013).

Kim, S., K-P Wu, and J. Baum. “Fast hydrogen exchange affects ¹⁵N relaxation measurements in intrinsically disordered proteins”, J. Biomol NMR, 55(3), 249-56 (2013).

Narayanan, C., D.S. Weinstock, K-P Wu, J. Baum, and RM Levy. “Investigation of the Polymeric Properties of α-Synuclein and Comparison with NMR Experiments: A Replica Exchange Molecular Dynamics Study”, J. Chem Theory Comput., 3939-3942 (2012).

Kang, L., G.M. Moriarty, L.A. Woods, A.E. Ashcroft, S.E. Radford, and J. Baum. “N-terminal acetylation of α-synuclein induces increased transient helical propensity and decreased aggregation rates in the intrinsically disordered monomerProtein Sci., 7, 911-7 (2012).

Xiao, J., B. Madhan, Y. Li, B. Brodsky, and J. Baum. “Osteogenesis imperfecta model peptides: incorporation of residues replacing Gly within a triple helix achieved by renucleation and local flexibility”, J. Biophysical, 101(2), 449-58 (2011).

Xiao, J., H. Cheng, T. Silva, J. Baum, and B. Brodsky. “Osteogenesis imperfecta missense mutations in collagen: structural consequences of a glycine to alanine replacement at a highly charged site”, Biochemistry, 50, 10771-80 (2011).

Kang, L., K-P Wu, M. Vendruscolo, and J. Baum. “The A53T mutation is key in defining the differences in the aggregation kinetics of human and mouse α-synuclein”, J Am Chem Soc., 133(34):13465-70 (2011).

Wu, K-P, and J. Baum. “Backbone assignment and dynamics of human α-synuclein in viscous 2 M glucose solution”, Biomol NMR Assign., 5(1), 43-6 (2011).

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